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The Subtype Specificity of Genetic Loci Associated with Stroke in 16,664 cases and 32,792 controls

By Matthew Traylor, Christopher D Anderson, Loes C.A. Rutten-Jacobs, Guido J. Falcone, Mary E. Comeau, Hakan Ay, Cathie LM Sudlow, Huichun Xu, Braxton Mitchell, John Cole, Kathryn Rexrode, Jordi Jimenez-Conde, Reinhold Schmidt, Raji P. Grewal, Ralph Sacco, Marta Ribases, Tatjana Rundek, Jonathan Rosand, Martin Dichgans, Lee Jin-Moo, Carl D. Langefeld, Steven J. Kittner, Hugh Stephen Markus, Daniel Woo, Rainer Malik, on behalf of the NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)

Posted 20 Jul 2018
bioRxiv DOI: 10.1101/371153 (published DOI: 10.1161/CIRCGEN.118.002338)

Background: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischaemic and haemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. Methods: We performed Bayesian multinomial regression in 16,664 stroke cases and 32,792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under two commonly used stroke classification systems, Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS). All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. Results: Sixteen loci were considered for analysis. Seven loci influenced both haemorrhagic and ischaemic stroke, three of which influenced ischaemic and haemorrhagic subtypes under both TOAST and CCS. Under CCS, 4 loci influenced both small vessel stroke and intracerebral haemorrhage. An EDNRA locus demonstrated opposing effects on ischaemic and haemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction and only one locus (12q24) was predicted to influence all ischaemic stroke subtypes. Conclusions: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between haemorrhagic and ischaemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

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